Severe H1N1 Infection in a Pediatric Liver Transplant Recipient Treated With Intravenous Zanamivir: Efficiency and Complications

The 2009 emerged pandemic influenza H1N1 is a leading cause for respiratory illness in children. Herein, we report about the first pediatric patient who developed severe bilateral pneumonia with acute respiratory distress syndrome caused by novel influenza H1N1 after liver transplantation. The 2-year-old child received a deceased whole organ liver transplantation because of end-stage Caroli's disease. Early postoperative course was complicated by portal vein thrombosis, which was successfully treated by thrombectomy 12 hr after transplantation. Immunosuppression was started with cyclosporine A (CSA; 50 mg/m2 intravenously [IV]; trough blood level 180–230 ng/mL), prednisone (15 mg/m2), and two doses of basiliximab (10 mg on days 0 and 4). Respiratory deterioration occurred 4 days after transplantation. The patient required invasive ventilation and developed adult respiratory distress syndrome (bilateral infiltrates on chest x-ray, PaO2/FiO2 150). Other symptoms were leukopenia and fever. Liver enzymes and function remained stable. Extended bacterial, viral, and fungal diagnostic workup from tracheal secretions revealed positive pandemic H1N1 RNA detected by polymerase chain reaction (PCR). Treatment with oseltamivir (2×30 mg/day) was started immediately after reception of positive H1N1 results at day 3 after the onset of first respiratory symptoms. Because the respiratory situation further deteriorated (PaO2/FiO2<100) and the patient developed gastroparesis, absorption of oseltamivir became questionable. IV zanamivir (2×260 mg/day) was started as “compassionate use” for 5 days from days 10 to 15 after transplantation. Parents gave informed consent, but institutional review board approval could not be achieved because treatment decision was made 2 days before Christmas. The treatment course neither led to negative H1N1 PCR nor to respiratory improvement. CSA was discontinued, and prednisone was reduced to 10 mg/m2 at day 11 after transplantation. The H1N1 virus tested was susceptible to oseltamivir and zanamivir. Mutations known to be associated with an enhanced pathogenicity were not identified by sequencing analysis. During the treatment with zanamivir, the patient's liver function worsened as indicated by the increase of serum aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) up to 628 U/L and 193 U/L, respectively. Ultrasound revealed an unexplained retrograde flow of the portal vein but no evidence of portal vein thrombosis. Rejection was ruled out by liver biopsy. Pandemic H1N1 RNA was not detectable in the liver biopsy. To improve the venous outflow of the liver, positive end-expiratory pressure (maximum 16 cm H2O) was gradually reduced without any effect. Portal vein flow normalized 10 days after stopping zanamivir. During zanamivir treatment, serum creatinine level increased from 0.36 mg/dL to a maximum of 0.68 mg/dL. Kidney function normalized with termination of zanamivir. Oseltamivir was continued for another 10 days. The patient improved slowly and was weaned from mechanical ventilation after 25 days. Pandemic H1N1 RNA in tracheal aspirate became negative 22 days after first detection. Although the majority of cases of pandemic H1N1 infections in children are mild, severe courses have been described, especially in children with comorbidities (1). Until August 2009, 36 deaths had been occurred in children younger than 18 years in the United States (2). Usually treatment of the influenza A virus with the oral preparation oseltamivir is effective to shorten the illness when initiated within 48 hr after first symptoms (3). The neuraminidase inhibitor, zanamivir, developed for IV use is not currently commercially available. In patients with severe illness and a known resistance of pandemic H1N1 to oseltamivir or in patients not tolerating enteral nutrition, this therapy might be an important alternative. Recently, a first case report with successful administration of zanamivir in a child with acute lymphoblastic leukemia has been published (4). In the presented case, zanamivir treatment was initiated as “compassionate use” because of progressive worsening of respiratory symptoms and severe gastroparesis, leading to questionable oseltamivir absorption. However, we were unable to demonstrate any positive effect as neither the symptoms improved nor the PCR became negative. A possible explanation might be the late start of the medication. Conversely, it cannot be excluded that the otherwise unexplained retrograde portal vein flow and kidney injury were caused by the medication. We believe that the coincidence in time of worsening liver function and zanamivir treatment makes a causal relationship at least possible. Duration of treatment with neuraminidase inhibitors was totally 20 days. A prolonged period of treatment is consistent with current published guidelines (5), which recommend treatment in transplant patients until H1N1 PCR becomes negative. Recommendations are based on the fact that viral shedding is prolonged in immunocompromised patients. Conversely, these potential benefits have to outweigh the risk of resistance emergence. Probably, the most important actions for improvement of clinical course in our patient were aggressive ventilatory support and the reduction of immunosuppression, especially the discontinuation of CSA. The presented case also underlines the fact that immunization against pandemic H1N1 should be recommended strongly to the patients on waiting list for organ transplantation (6). Furthermore, vaccination programs for healthcare professionals are emphasized strongly, because our patient was probably infected by a doctor, nurse, or physiotherapist. In conclusion, in other cases, zanamivir has been proven to be effective to shorten pandemic H1N1 influenza illness. If given late in the disease course (>48 hr after onset of symptoms), caregivers have to balance the reduced efficiency against possible toxic side effects. Christian Dohna-Schwake1 Brunhilde Schweiger2 Ursula Felderhoff-Müser1 Melanie Fiedler3 Gernot M. Kaiser4 Andreas Paul4 Patrick Gerner1 Elke Lainka1 Peter F. Hoyer1 1 University Children's Hospital University of Duisburg-Essen Essen, Germany 2 Robert Koch Institute National Reference Center Influenza Berlin, Germany 3 Institute of Virology University of Duisburg-Essen Essen, Germany 4 Department of General, Visceral and Transplant Surgery University of Duisburg-Essen Essen, Germany